Phase 1 and Phase 2 clinical trials of a new class of redox-active pharmaceutical are proposed in high-grade glioma (WHO grade III and IV). This project will test a compound that crosses the blood-brain barrier and which prevents hippocampal stem cell loss and white matter degradation following radiation therapy (RT). The compound also inhibits tumor regrowth following RT and thus has the dual impact of protecting normal tissues while improving tumor treatment responses. This drug is both neuroprotective against RT and a radio sensitizer that is expected to enhance inhibition of glioblastoma by RT. Primary brain tumors represent 1% of all diagnosed cancers. Even though these tumors represent a rare malignancy, high-grade gliomas are aggressive and lethal and are associated with severe disabling central nervous system involvement. Cognition and neurological function are compromised at diagnosis and during treatment. The standard of care for newly diagnosed high-grade gliomas involves surgical resection, followed by RT with concurrent temozolomide (TMZ). Despite aggressive treatment, nearly all patients with the most common form of adult primary brain tumor, glioblastoma (WHO grade IV), die of disease progression; median survival is 9-15 months after diagnosis. Most high-grade gliomas are resistant to current available therapies. Thus, a major requirement for the next generation therapy of primary brain tumors requires more effective tumor control and protection against the neurotoxicity. The objective of this proposed project is to test the hypothesis that a new class of redox-active metalloporphyrins is an effective radio protector and tumor sensitizer in brain tissue. The specific aims are to: 1) perform a Phase 1 clinical trial of this new drug in combination with standard RT and TMZ in newly diagnosed high-grade glioma patients, and 2) perform a randomized open-label Phase 2 clinical trial of the new drug in combination with standard RT and TMZ versus standard RT and TMZ alone in patients with newly diagnosed high-grade glioma patients. The primary outcome is protection/improvement of cognition. This new class of drug has the potential to protect against deterioration of cognition and improve health-related quality of life in high-grade glioma patients undergoing RT and chemotherapy, while also enhancing patient survival.